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Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort
Open accessAbstract
OBJECTIVE: Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. METHOD: We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. RESULTS: ), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). CONCLUSIONS: The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.
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“Variants in the IL6R gene have been found to be associated with increased risk of coronary artery disease24, rheumatoid arthritis, atrial fibrillation, and abdominal aortic aneurysm, and with increased susceptibility to asthma, type 1 diabetes, and depression36,37.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [36]
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Metadata
- Authors
- Khandaker, G. M., Zammit, S., Burgess, S., Lewis, G., & Jones, P. B.
- Affiliations
- University of Cambridge (GB)
- University of Bristol (GB)
- University College London (GB)
- Corresponding author
- Khandaker, Golam M.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 69
- Pages
- 264-272
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5871397
- OpenAlex
- W2774979768
- Cited by
- 118
- References
- 67
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 17 · 2020: 20 · 2019: 18 · 2018: 10
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (204623/Z/16/Z, 102215/2/13/2), 088869/Z/09/Z, 095844/Z/11/Z, 088869, 102215, /Z/11/Z, 100114, 102215/2/13/, 201486 /Z/16/Z, 80354, 201486, 100114/Z/12/Z, 095844)
- NIHR Bristol Biomedical Research Centre
- National Institute for Health and Care Research (NF-SI-0617-10113, NF-SI-0512-10165, RP-PG-0606-1335)
- British Heart Foundation (RG/13/13/30194)
- Academy of Medical Sciences (AMS-SGCL13-Khandaker, 80354)
- University of Bristol (102215/2/13/2, 201486/Z/16/Z)
- Medical Research Council (102215, ref: 102215/2/13/2, MR/L003120/1, 201486/Z/16/Z, 102215/2/13/2, MR/L010305/1, MC_PC_15018)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- IL-6 receptor, rs2228145, depression, psychosis, interleukin-6, C-reactive protein, inflammation, genetic susceptibility, ALSPAC birth cohort, childhood risk factors, postpartum depression
- MeSH terms
- Adolescent, C-Reactive Protein, Child, Depressive Disorder, Female, Genotype, Humans, Male, Psychotic Disorders, Cohort Studies, Interleukin-6, Receptors, Interleukin-6, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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